PROJECT ABSTRACT The main research goal of this award is to characterize the burden of type 2 diabetes mellitus (T2DM) and its impact on tuberculosis (TB) risk among HIV-positive adults in Durban, South Africa. We will compare these results to a comparable HIV-negative population in Durban. We will also investigate the impact of T2DM on HIV and TB outcomes and use these results to inform future training grants and translational research. TB is the leading infectious cause of mortality globally. Approximately 15% of all TB cases are attributable to T2DM, and similarly 15% are attributable to HIV. The prevalence of diabetes continues to increase globally, most rapidly in low- and middle-income countries. T2DM increases the risk of TB by 3-times, but among diabetic patients with successful glycemic control this risk of TB is effectively mitigated. HIV clinical care programs in high HIV burden settings are uniquely positioned to facilitate diagnosis and treatment of T2DM, which could improve HIV, TB, and T2DM outcomes. However, epidemiological research describing the burden of T2DM among HIV- positive adults in sub-Saharan Africa is sparse and estimation of its impact on HIV and TB outcomes in high burden settings is much needed guide the integration of HIV and T2DM screening and treatment programs. This F31 proposal will fill important information gaps through three specific aims using data from an ongoing cohort study of HIV-positive adults in the Umlazi township of Durban, South Africa and the completed population-based Durban Diabetes Study, which included HIV-negative adults. First, we will characterize the burden of T2DM by HIV status and use a propensity score stratification to assess the impact of T2DM on key HIV outcomes (i.e. HIV viral load, CD4 recovery, hospitalizations, death over 12 months of follow-up). Second, we will test the impact of T2DM and pre-diabetes on TB risk overall and by HIV status, and investigate the impact on TB treatment outcomes using doubly robust inverse probability of treatment weighting and generalized estimating equations. Finally, we will incorporate the effects of HIV-infection, glycemic control, and body mass index into a previously published mathematical model of the T2DM-TB relationship in order to estimate the 20 year population-level impact of T2DM on TB incidence in this high HIV burden setting. This proposed NIH F31 mentored research training grant will support Ms. Kubiak as she furthers her pre- doctoral training at the University of Washington's Department of Epidemiology through focused training and applying advanced statistical and mathematical modeling techniques, relevant content knowledge in diabetes and immunology, the ethical conduct of research, and dissemination of scientific results. She will receive mentorship from Drs. Paul Drain, Annette Fitzpatrick, Ruanne Barnabas, Mario Kratz, Connie Celum, Deborah Donnell, Ayesha Motala, and Yunus Moosa. With her previous international research experience, outstanding mentorship team, and carefully crafted research training plan to further develop her expertise, Ms. Kubiak will have a strong foundation to contribute to the control of HIV, TB, and diabetes epidemics in resource-limited settings as an independent investigator.